PB2258: PHASE 1 FIRST IN HUMAN STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF GRC54276, A NOVEL HPK1 THRONINE-KINASE INHIBITOR, IN ADVANCED SOLID TUMOURS AND LYMPHOMAS.
Authors: Harsha Doddihal, Thomas Marron, Satheesh C T, Manuprasad Avaronnan, Rajnish Nagarkar, Vineet Govinda Gupta, Biju Benjamin, Nagaraj Gowda, Venkatesha Udupa, Nilanjana Biswas, Jatin Kadam, Priyanka Dhage, Adam Beltran, Nikhil Amin
Journal: HemaSphere (2023)

Topic: 17. Hodgkin lymphoma - Clinical Background: Hematopoietic progenitor kinase 1, is a member of the MAP4K family of protein serine/threonine kinases. HPK1 mediates its negative regulation of T cell receptor (TCR) and B cell receptor (BCR) by phosphorylating the serine 376 residue of SLP76 and the threonine residue 152 of BLNK, respectively. GRC54276 is a potent HPK1 inhibitor. Inhibition of HPK1 alone is expected to enhance immune response to cancer and, when used in combination, with immune checkpoint inhibitors (ICIs) such as programed cell death-ligand 1 (PD-L1) blocking antibodies, it may improve responses to these standard immunotherapies. Preclinical studies have shown beneficial tumor response to GRC 54276 as a monotherapy and also improved efficacy when combined with atezolizumab and monoclonal antibody constructs similar to pembrolizumab. Aims: ●Primary objective: To determine the safety and tolerability of GRC 54276 as a monotherapy and in combination with pembrolizumab or atezolizumab and to establish the Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D) as a single agent and in combination therapy. To study the pharmacokinetic profile of GRC54276. ●Secondary objective: Evaluate efficacy parameters of GRC54276 as a monotherapy and in combination with pembrolizumab or atezolizumab Methods: GRC54276-101 is an ongoing phase 1, first in human (FIH), open label, multicenter study evaluating the safety, tolerability, PK and efficacy of GRC54276 as a single agent and in combination with pembrolizumab or atezolizumab. Part 1 is the dose escalation 3 + 3 design, consisting of part 1a (monotherapy) and part 1b (combination). Part 2 is the dose expansion phase. Key inclusion criteria for part 1 are patients with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors or lymphomas who have previously received standard systemic therapy or for whom treatment is not accessible, not tolerated or refused, have progressed ≥ 1 of systemic therapies for recurrent/ metastatic disease. The patient population for part 2 will be defined after the completion of part 1a and part 1b. As of December 1st 2022, 11 patients have been recruited in the monotherapy 3 + 3 dose escalation. Results: 11 patients (4 males, 7 females) were enrolled in the first two dose cohorts, 8 patients in the 50 mg cohort and 3 patients in the 75 mg cohort. Tumor types: biliary duct cancer (1), breast cancer (3), buccal mucosa (2), cervical carcinoma (1), colon cancer (2), Hodgkin’s lymphoma (1) and ovarian cancer (1). Patients had a median of 3.5 lines of prior therapy, (range:1-11). Median treatment duration on GRC54276 was 42 days (range:14-120). No DLTs were observed during the DLT observation period of both 50 mg and 75 mg cohort. 6 patients reported 22 treatment related adverse events. 2 patients reported 4 treatments related AEs ≥ Grade 3, 6 patients reported ≤Grade 2 AEs. Tumor response was evaluable in 5 patients. One patient of Hodgkin’s lymphoma had partial response at 6 weeks and progressed at 18 weeks. Two patients, one of colon cancer and one of buccal mucosal cancer had stable disease at 6 weeks persisting at 18 weeks. 2 patients had progressive disease at 6 weeks. Summary/Conclusion: GRC54276 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to Hodgkin’s lymphoma, colon carcinoma and buccal mucosal carcinoma patients. GRC54276 will be further tested in select patients as monotherapy and in combination with pembrolizumab or atezolizumab. Keywords: Lymphoma, Targeted therapy, Hodgkin’s lymphoma, Cancer immunotherapy